Embolization

ABSTRACT

A composition includes a plurality of particles. At least some of the plurality of particles include cross-linked polyvinyl alcohol and have a diameter of about 500 microns or less. The particles have a first average pore size in an interior region, and a second average pore size at a surface region. The first average pore size being greater than the second average pore size. The composition also includes a carrier fluid. The plurality of particles being in the carrier fluid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of and claims priority under35 U.S.C. §120 to U.S. patent application Ser. No. 10/215,594, filedAug. 9, 2002, and entitled “Embolization,” and U.S. patent applicationSer. No. 10/615,276, filed Jul. 8, 2003, and entitled “Agent DeliveryParticle,” which are both incorporated herein by reference.

TECHNICAL FIELD

The invention relates to embolization.

BACKGROUND

Therapeutic vascular occlusions (embolizations) are used to prevent ortreat pathological conditions in situ. Compositions including embolicparticles are used for occluding vessels in a variety of medicalapplications. Delivery of embolic particles through a catheter isdependent on size uniformity, density and compressibility of the embolicparticles.

SUMMARY

In one aspect, the invention features a polymeric particle having adiameter of about 500 microns or less. The particle has a first densityof pores in an interior region and a second density of pores at asurface region. The first density is different from the second density.

In another aspect, the invention features a polymeric particle having adiameter of about 500 microns or less. The particle has a first averagepore size in an interior region and a second average pore size at thesurface region. The first average pore size is different from the secondaverage pore size.

In a further aspect, the invention features a composition that includesa plurality of particles in a carrier fluid. At least some of theplurality of particles have a diameter of about 500 microns or less. Atleast some of the particles having a diameter of about 500 microns orless have a first density of pores in an interior region and a seconddensity of pores at a surface region. The first density is differentfrom the second density.

In one aspect, the invention features a composition that includes aplurality of particles in a carrier fluid. At least some of theplurality of particles have a diameter of about 500 microns or less. Atleast some of the particles having a diameter of about 500 microns orless have a first average pore size in an interior region and a secondaverage pore size at a surface region. The first average pore size isdifferent from the second average pore size.

In another aspect, the invention features a method that includes passinga solution that contains a base polymer and a gelling precursor throughan orifice having a diameter of about 200 microns or less (e.g., about100 microns or less, about 10 microns or more) to form drops containingthe base polymer and the gelling precursor. The method also includesforming particles containing the base polymer and the gelling precursorfrom the drops containing the base polymer and the gelling precursor.

In a further aspect, the invention features a method that includesheating a solution that contains a base polymer and a gelling precursorto a temperature of at least about 50° C. (e.g., about 65° C. or more,about 75° C. or more, about 85° C. or more, about 95° C. or more, about105° C. or more, about 115° C. or more, about 121° C.). The method alsoinclude forming particles containing the base polymer and the gellingprecursor from the solution containing the base polymer and the gellingprecursor.

In one aspect, the invention features a method that includes passing asolution containing a base polymer and a gelling precursor through anorifice while vibrating the orifice at a frequency of about 0.1 KHz ormore (e.g., about 0.8 KHz or more, about 1.5 KHz or more) to form dropscontaining the base polymer and the gelling precursor. The method alsoincludes forming particles containing the base polymer and the gellingprecursor from the drops containing the base polymer and the gellingprecursor.

In another aspect, the invention features a method that includes formingdrops containing the base polymer and the gelling precursor, andcontacting the drops with a gelling agent to form particles containingthe base polymer and the gelling precursor. The gelling agent is at atemperature greater than room temperature (e.g., a temperature of about30° C. or more).

In a further aspect, the invention features a method that includesforming drops containing a base polymer and a gelling precursor, andcontacting the drops with a gelling agent to form particles containingthe base polymer and the gelling precursor. The gelling agent iscontained in a vessel, and the method further includes bubbling a gasthrough the gelling agent, disposing a mist containing the gelling agentbetween a source of the drops and the vessel, including a surfactant inthe mixture containing the gelling agent, and/or stirring the gellingagent.

In one aspect, the invention features a method that includesadministering to a subject a therapeutically effective amount of acomposition including a plurality of particles in a carrier fluid. Atleast some of the plurality of particles have a diameter of about 500microns or less. At least some of the particles having a diameter ofabout 500 microns or less have a first density of pores in an interiorregion and a second density of pores at a surface region. The firstdensity is different from the second density.

In another aspect, the invention features a method that includesadministering to a subject a therapeutically effective amount of acomposition including a plurality of particles in a carrier fluid. Atleast some of the plurality of particles have a diameter of about 500microns or less. At least some of the particles having a diameter ofabout 500 microns or less have a first average pore size in an interiorregion and a second average pore size at a surface region. The firstaverage pore size is different from the second average pore size.

Embodiments may also include one or more of the following.

The first density can be greater than the second density.

The first average pore size can be greater than the second average poresize.

A particle can have a diameter of about 10 microns or more. A particlecan have a diameter of about 100 microns or more and/or a diameter ofabout 300 microns or less. A particle can have a diameter of about 300microns or more.

A particle can include at least one polymer selected from polyvinylalcohols, polyacrylic acids, polymethacrylic acids, poly vinylsulfonates, carboxymethyl celluloses, hydroxyethyl celluloses,substituted celluloses, polyacrylamides, polyethylene glycols,polyamides, polyureas, polyurethanes, polyesters, polyethers,polystyrenes, polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids, andpoly(lactic-co-glycolic) acids.

A particle can be at least partially coated with a substantiallybioabsorbable material.

A particle can have a density of from about 1.1 grams per cubiccentimeter to about 1.4 grams per cubic centimeter.

A particle can have a sphericity of about 0.9 or more.

After compression to about 50 percent, a particle has a sphericity ofabout 0.9 or more.

A particle can include about 2.5 weight percent or less polysaccharide(e.g., alginate). An alginate can have a guluronic acid content of about60 percent or greater.

A particle can be substantially insoluble in DMSO.

A particle can be substantially free of animal-derived compounds.

A carrier fluid can include a saline solution, a contrast agent or both.

A plurality of particles can have a mean diameter of about 500 micronsor less and/or about 10 microns or more. A plurality of particles canhave a mean diameter of about 100 microns or more and/or a mean diameterof about 300 microns or less. A plurality of particles can have a meandiameter of about 300 microns or more.

A method can include heating the solution to a temperature of at leastabout 50° C. before passing the solution through the orifice.

A method can include vibrating the nozzle orifice at a frequency of atleast about 0.1 KHz as the solution passes therethrough.

A method can further include contacting the drops with a gelling agentto gel the gelling precursor to form particles comprising the basepolymer and gelled gelling precursor.

A method can further include removing at least some of the gelledgelling precursor from the particles.

A composition can be administered by percutaneous injection.

A composition can be administered by a catheter.

A composition can be introduced into the subject using a lumen having adiameter that is smaller than a mean diameter of the plurality ofparticles.

A composition can be used to treat a cancer condition. The cancercondition can be, for example, ovarian cancer, colorectal cancer,thyroid cancer, gastrointestinal cancer, breast cancer, prostate cancerand/or lung cancer. Treating the cancer condition can include at leastpartially occluding a lumen providing nutrients to a site of the cancercondition with at least some of the plurality of particles.

A method can include at least partially occluding a lumen in the subjectwith at least some of a plurality of particles.

Embodiments of the invention may have one or more of the followingadvantages. Some disorders or physiological conditions can be mediatedby delivery of embolic compositions. Embolic compositions can be used,for example, in treatment of fibroids, tumors (e.g., hypervasculartumors), internal bleeding, and/or arteriovenous malformations (AVMs).Examples of fibroids can include uterine fibroids which grow within theuterine wall, on the outside of the uterus, inside the uterine cavity,between the layers of broad ligament supporting the uterus, attached toanother organ or on a mushroom-like stalk. Internal bleeding includesgastrointestinal, urinary, renal and varicose bleeding. AVMs are, forexample, abnormal collections of blood vessels which shunt blood from ahigh pressure artery to a low pressure vein. The result can be hypoxiaand malnutrition of those regions from which the blood is diverted.

Spherical embolic particles in the embolic compositions can be tailoredto a particular application by, for example, varying particle size,porosity gradient, compressibility, sphericity and density of theparticles. In embodiments in which the spherical embolic particles havea substantially uniform size, the particles can, for example, fitthrough the aperture of a catheter for administration by injection to atarget site, without partially or completely plugging the lumen of thecatheter. The spherical embolic particles have a mean diameter of about1200 microns or less (e.g., from about 100 microns to about 500microns). Size uniformity of ±15 percent of the spherical embolicparticles allows the particles to stack evenly in the cylindrical lumenof the blood vessel to completely occlude the blood vessel lumen.Suspensions containing the embolic particles at a density of about 1.1grams per cubic centimeter to about 1.4 grams per cubic centimeter canbe prepared in calibrated concentrations of the embolic particles forease of delivery by the physician without rapid settlement of thesuspension. Control in sphericity and uniformity of the embolicparticles can result in reduction in aggregation caused, for example, bysurface interaction of the particles. In addition, the embolic particlesare relatively inert in nature.

Features and advantages are in the description, drawings, and claims.

DESCRIPTION OF DRAWINGS

FIG. 1A is a schematic illustrating injection of an embolic compositionincluding embolic particles into a vessel, while FIG. 1B is an enlargedview of the region 1B in FIG. 1A;

FIG. 2A is a light micrograph of a collection of hydrated embolicparticles, while FIG. 2B is a scanning electron microscope (SEM)photograph of an embolic particle surface and FIGS. 2C-2E arecross-sections of embolic particles;

FIG. 3A is a schematic of the manufacture of an embolic compositionwhile FIG. 3B is an enlarged schematic of region 3B in FIG. 3A;

FIG. 4 is a photograph of gel-stabilized drops;

FIG. 5 is a graph of embolic particle size uniformity;

FIG. 6 is a graph of embolic particle size uniformity;

FIG. 7 is a schematic of an injection pressure testing equipment;

FIG. 8 is an infrared spectrum of embolic particles; and

FIG. 9 is an infrared spectrum of embolic particles.

DETAILED DESCRIPTION Composition

Referring to FIGS. 1A and 1B, an embolic composition, including embolicparticles 111 and a carrier fluid, is injected into a vessel through aninstrument such as a catheter 150. Catheter 150 is connected to asyringe barrel 110 with a plunger 160. Catheter 150 is inserted, forexample, into a femoral artery 120 of a patient. Catheter 150 deliversthe embolic composition to, for example, occlude a uterine artery 130leading to a fibroid 140. Fibroid 140 is located in the uterus of afemale patient. The embolic composition is initially loaded into syringe110. Plunger 160 of syringe 110 is then compressed to deliver theembolic composition through catheter 150 into a lumen 165 of uterineartery 130.

Referring particularly to FIG. 1B which is an enlarged view of section1B of FIG. 1A, uterine artery 130 is subdivided into smaller uterinevessels 170 (e.g., having a diameter of about 2 millimeters or less)which feed fibroid 140. The embolic particles 111 in the emboliccomposition partially or totally fill the lumen of uterine artery 130,either partially or completely occluding the lumen of the uterine artery130 that feeds uterine fibroid 140.

In general, the particles are substantially formed of a polymer, such asa highly water insoluble, high molecular weight polymer. An example ofsuch a polymer is a high molecular weight polyvinyl alcohol (PVA) thathas been acetalized. The embolic particles can be substantially pureintrachain 1,3-acetalized PVA and substantially free of animal derivedresidue such as collagen. In embodiments, the particles include a minoramount (e.g., about 2.5 weight percent or less, about one weight percentor less, about 0.2 weight percent or less) of a gelling material (e.g.,a polysaccharide, such as alginate).

FIG. 2A shows an embodiment in which the embolic particles have asubstantially uniform spherical shape and size. FIG. 2B shows anembodiment in which an embolic particle has a well-defined outerspherical surface including relatively small, randomly located pores.The surface appears substantially smooth, with a surface morphologyincluding larger features, such as crevice-like features. FIGS. 2C-2Eshow scanning electron micrograph (SEM) images of cross-sections throughembolic particles in which the bodies of the particles define poreswhich provide compressibility and other properties to the emboliccomposition. Pores near the center of the particle are relatively large,and pores near the surface of the particle are relatively small.

The region of small pores near the surface of the embolic particle isrelatively stiff and incompressible, which enhances resistance to shearforces and abrasion. In addition, the variable pore size profile canproduce a symmetric compressibility and, it is believed, acompressibility profile. As a result, the particles can be relativelyeasily compressed from a maximum, at rest diameter to a smaller,compressed first diameter, although compression to an even smallerdiameter requires substantially greater force. Without wishing to bebound by theory, it is believed that a variable compressibility profilecan be due to the presence of a relatively weak, collapsible inter-porewall structure in the center region where the pores are large, and astiffer inter-pore wall structure near the surface of the particle,where the pores are more numerous and relatively small. It is furtherbelieved that a variable pore size profile can enhance elastic recoveryafter compression. It is also believed that the pore structure caninfluence the density of the embolic particles and the rate of carrierfluid or body fluid uptake.

In some embodiments, the embolic particles can be delivered through acatheter having a lumen with a cross-sectional area that is smaller(e.g., about 50 percent or less) than the uncompressed cross-sectionalarea of the particles. In such embodiments, the embolic particles arecompressed to pass through the catheter for delivery into the body.Typically, the compression force is provided indirectly, by depressingthe syringe plunger to increase the pressure applied to the carrierfluid. In general, the embolic particles are relatively easilycompressed to diameters sufficient for delivery through the catheterinto the body. The relatively robust, rigid surface region can resistabrasion when the embolic particles contact hard surfaces such assyringe surfaces, hard plastic or metal stopcock surfaces, and thecatheter lumen wall (made of, e.g., Teflon) during delivery. Once in thebody, the embolic particles can substantially recover to originaldiameter and shape for efficient transport in the carrier and body fluidstream. At the point of occlusion, the particles can again compress asthey aggregate in the occlusion region. The embolic particles can form arelatively dense occluding mass. The compression in the body isgenerally determined by the force provided by body fluid flow in thelumen. In some embodiments, the compression may be limited by thecompression profile of the particles, and the number of embolicparticles needed to occlude a given diameter may be reduced.

In some embodiments, among the particles delivered to a subject, themajority (e.g., about 50 percent or more, about 60 percent or more,about 70 percent or more, about 80 percent or more, about 90 percent ormore) of the particles have a diameter of about 1500 microns or less(e.g., about 1200 microns or less, about 900 microns or less, about 700microns or less, about 500 microns or less, about 300 microns or less)and/or about 10 microns or more (e.g., about 100 microns or more, about300 microns or more, about 400 microns or more, about 500 microns ormore, about 700 microns or more, about 900 microns or more).

In certain embodiments, the particles delivered to a subject have a meandiameter of about 1500 microns or less (e.g., about 1200 microns orless, about 900 microns or less, about 700 microns or less, about 500microns or less, about 300 microns or less) and/or about 10 microns ormore (e.g., about 100 microns or more, about 300 microns or more, about400 microns or more, about 500 microns or more, about 700 microns ormore, about 900 microns or more). Exemplary ranges for the mean diameterof particles delivered to a subject include from about 100 microns toabout 300 microns, from about 300 microns to about 500 microns, fromabout 500 microns to about 700 microns, and from about 900 microns toabout 1200 microns. In general, a collection of particles has a meandiameter in approximately the middle of the range of the diameters ofthe individual particles, and a variance of about 20 percent or less(e.g. about 15 percent or less, about 10 percent or less).

In some embodiments, the mean size of the particles delivered to asubject can vary depending upon the particular condition to be treated.As an example, in embodiments in which the particles are used to treat aliver tumor, the particles delivered to the subject can have a meandiameter of about 500 microns or less (e.g., from about 100 microns toabout 300 microns, from about 300 microns to about 500 microns). Asanother example, in embodiments in which the particles are used to treata uterine fibroid, the particles delivered to the subject can have amean diameter of about 1200 microns or less (e.g., from about 500microns to about 700 microns, from about 700 microns to about 900microns, from about 900 microns to about 1200 microns).

As shown in FIG. 2C, in some embodiments a particle can be considered toinclude a center region, C, from the center c′ of the particle to aradius of about r/3, a body region, B, from about r/3 to about 2 r/3 anda surface region, S, from 2r/3 to r. The regions can be characterized bythe relative size of the pores in each region, the density of the pores(the number of pores per unit volume) in each region, and/or thematerial density (density of particle material per unit volume) in eachregion.

In general, the mean size of the pores in region C of a particle isgreater than the mean size of the pores at region S of the particle. Insome embodiments, the mean size of the pores in region C of a particleis greater than the mean size of the pores in region B the particle,and/or the mean size of the pores in region B of a particle is greaterthan the mean size of the pores at region S the particle. In someembodiments, the mean pore size in region C is about 20 microns or more(e.g., about 30 microns or more, from about 20 microns to about 35microns). In certain embodiments, the mean pore size in region B isabout 18 microns or less (e.g. about 15 microns or less, from about 18microns to about two microns). In some embodiments, the mean pore sizeof the pores in region S is about one micron or less (e.g. from about0.1 micron to about 0.01 micron). In certain embodiments, the mean poresize in region B is from about 50 percent to about 70 percent of themean pore size in region C, and/or the mean pore size at region S isabout 10 percent or less (e.g., about two percent or less) of the meanpore size in region B. In some embodiments, the surface of a particleand/or its region S is/are substantially free of pores having a diametergreater than about one micron (e.g., greater than about 10 microns). Incertain embodiments, the mean pore size in the region from 0.8r to r(e.g., from 0.9r to r) is about one micron or less (e.g., about 0.5micron or less, about 0.1 micron or less). In some embodiments, theregion from the center of the particle to 0.9r (e.g., from the center ofthe particle to 0.8r) has pores of about 10 microns or greater and/orhas a mean pore size of from about two microns to about 35 microns. Incertain embodiments, the mean pore size in the region from 0.8r to r(e.g., from 0.9r to r) is about five percent or less (e.g., about onepercent or less, about 0.3 percent or less) of the mean pore size in theregion from the center to 0.9r. In some embodiments, the largest poresin the particles can have a size in the range of about one percent ormore (e.g., about five percent or more, about 10 percent or more) of theparticle diameter. The size of the pores in a particle can be measuredby viewing a cross-section as in FIG. 2C. For irregularly shaped(nonspherical) pores, the maximum visible cross-section is used. In FIG.2C, the SEM was taken on wet particles including absorbed saline, whichwere frozen in liquid nitrogen and sectioned. FIG. 2B was taken prior tosectioning. In FIGS. 2D-2E, the particle was freeze-dried prior tosectioning and SEM analysis.

Generally, the density of pores in region C of a particle is greaterthan the density of pores at region S of the particle. In someembodiments, the density of pores in region C of a particle is greaterthan the density of pores in region B of the particle, and/or thedensity of pores in region B of a particle is greater than the densityof pores at region S of the particle.

In general, the material density in region C of a particle is less thanthe material density at region S of the particle. In some embodiments,the material density in region C of a particle is less than the materialdensity in region B of the particle, and/or the material density inregion B of a particle is less than the material density at region S ofthe particle.

In general, the density of a particle (e.g., as measured in grams ofmaterial per unit volume) is such that it can be readily suspended in acarrier fluid (e.g., a pharmaceutically acceptable carrier, such as asaline solution, a contrast solution, or a mixture thereof) and remainsuspended during delivery. In some embodiments, the density of aparticle is from about 1.1 grams per cubic centimeter to about 1.4 gramsper cubic centimeter. As an example, for suspension in a saline-contrastsolution, the density can be from about 1.2 grams per cubic centimeterto about 1.3 grams per cubic centimeter.

In certain embodiments, the sphericity of a particle after compressionin a catheter (e.g., after compression to about 50 percent or more ofthe cross-sectional area of the particle) is about 0.9 or more (e.g.,about 0.95 or more, about 0.97 or more). A particle can be, for example,manually compressed, essentially flattened, while wet to about 50percent or less of its original diameter and then, upon exposure tofluid, regain a sphericity of about 0.9 or more (e.g., about 0.95 ormore, about 0.97 or more).

Manufacture

FIG. 3A shows an embodiment of a system for producing embolic particles.The system includes a flow controller 300, a drop generator 310, agelling vessel 320, a reactor vessel 330, a gel dissolution chamber 340and a filter 350. As shown in FIG. 3B, flow controller 300 deliverspolymer solutions to a viscosity controller 305, which heats thesolution to reduce viscosity prior to delivery to drop generator 310.The solution passes through an orifice in a nozzle in drop generator310, forming drops of the solution. The drops are then directed intogelling vessel 320, where the drops are stabilized by gel formation. Thegel-stabilized drops are transferred from gelling vessel 320 to reactorvessel 330, where the polymer in the gel-stabilized drops is reacted,forming precursor particles. The precursor particles are transferred togel dissolution chamber 340, where the gel is dissolved. The particlesare then filtered in filter 350 to remove debris, and are sterilized andpackaged as an embolic composition including embolic particles.

In general, a base polymer and a gelling precursor are dissolved inwater and mixed.

Examples of base polymers include polyvinyl alcohols, polyacrylic acids,polymethacrylic acids, poly vinyl sulfonates, carboxymethyl celluloses,hydroxyethyl celluloses, substituted celluloses, polyacrylamides,polyethylene glycols, polyamides, polyureas, polyurethanes, polyesters,polyethers, polystyrenes, polysaccharides, polylactic acids,polyethylenes, polymethylmethacrylates, polycaprolactones, polyglycolicacids, poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic)acids) and copolymers or mixtures thereof A preferred polymer ispolyvinyl alcohol (PVA). The polyvinyl alcohol, in particular, istypically hydrolyzed in the range of from about 80 percent to about 99percent. The weight average molecular weight of the base polymer can be,for example, in the range of from about 9000 to about 186,000 (e.g.,from about 85,000 to about 146,000, from about 89,000 to about 98,000).

Gelling precursors include, for example, alginates, alginate salts,xanthan gums, natural gum, agar, agarose, chitosan, carrageenan,fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gumghatti, gum karaya, gum tragacanth, hyalauronic acid, locust beam gum,arabinogalactan, pectin, amylopectin, other water solublepolysaccharides and other ionically cross-linkable polymers. Aparticular gelling precursor is sodium alginate. A preferred sodiumalginate is high guluronic acid, stem-derived alginate (e.g., about 50percent or more, about 60 percent or more guluronic acid) with a lowviscosity (e.g., from about 20 centipoise to about 80 centipoise at 20°C.), which produces a high tensile, robust gel.

In some embodiments, the base polymer (e.g., PVA, such as high molecularweight PVA) can be dissolved in water by heating (e.g., above about 70°C. or more, about 121° C.), while the gelling precursor (e.g., analginate) can be dissolved at room temperature. The base polymer (e.g.,PVA) can be dissolved by mixing the base polymer and the gellingprecursor (e.g., alginate) together in a vessel which is heated, e.g.,to a temperature of at least about 50° C. (e.g., about 65° C. or more,about 75° C. or more, about 85° C. or more, about 95° C. or more, about105° C. or more, about 115° C. or more, about 121° C.). In someembodiments, the mixture can be heated in an autoclave. Alternatively,the base polymer (e.g., PVA) can be disposed in water and heated. Thegelling precursor (e.g., alginate) can subsequently be added at roomtemperature, to avoid exposing the alginate to high temperature. Heatcan also be applied, for example, by microwave application.

In certain embodiments, such as when the base polymer is PVA and thegelling precursor is alginate, the mixture can be from about 6.5 weightpercent to about 8.5 weight percent (e.g., about eight weight percent,about seven weight percent) base polymer and from about 1.5 weightpercent to about 2.5 weight percent (e.g., about 1.75 weight percent,about two weight percent) gelling precursor.

In some embodiments, the base polymer/gelling precursor mixture can beintroduced to a high pressure pumping apparatus, such as a syringe pump(e.g., model PHD4400, Harvard Apparatus, Holliston, Mass.), and thentransferred to drop generator 310. Alternatively or additionally, dropgenerator 310 can contain a pressure control device that applies apressure (e.g., from about 0.5 Bar to about 1.6 Bar) to the basepolymer/gelling precursor mixture (a pressure head) to control the rateat which the mixture is transferred to drop generator 310.

The pressure can be selected, for example, based on the size of thenozzle orifice and/or the desired viscosity of the base polymer/gellingprecursor mixture, and/or the desired size of the particles. In general,for a given mixture, as the nozzle orifice is decreased, the pressure isincreased. Generally, for a given mixture, as the desired viscosity ofthe mixture is decreased, the temperature is increased. As an example,in embodiments in which the nozzle orifice has a diameter of about 100microns and the base polymer/gelling precursor mixture has a viscosityof from about 60 centipoise to about 100 centipoise, the pressure can beabout 1.55 Bar. As another example, in embodiments in which the nozzleorifice has a diameter of about 200 microns and the base polymer/gellingprecursor mixture has a viscosity of from about 60 centipoise to about100 centipoise, the pressure can be about 0.55 Bar.

Referring to FIG. 3B, viscosity controller 305 is a heat exchanger thatcirculates water at a predetermined temperature about the flow tubingbetween the pump and drop generator 310. The base polymer/gellingprecursor mixture flows into viscosity controller 305, where the mixtureis heated so that its viscosity is lowered to a desired level.Alternatively or additionally, the vessel containing the basepolymer/gelling precursor mixture can be disposed in a heated fluid bath(e.g., a heated water bath) to heat the base polymer/gelling precursormixture. In some embodiments (e.g., when the system does not containviscosity controller 305), flow controller 300 and/or drop generator 310can be placed in a temperature-controlled chamber (e.g. an oven, a heattape wrap) to heat the base polymer/gelling precursor mixture.

The temperature to which the base polymer/gelling precursor mixture isheated prior to transfer to drop generator 310 can be selected, forexample, based on the desired viscosity of the mixture and/or the sizeof the orifice in the nozzle. In general, for a given mixture, the lowerthe desired viscosity of the mixture, the higher the temperature towhich the mixture is heated. Generally, for a given mixture, the smallerthe diameter of the nozzle, the higher the temperature to which themixture is heated. As an example, in embodiments in which nozzle has adiameter of from about 150 microns to about 300 microns and the desiredviscosity of the mixture is from about 90 centipoise to about 200centipoise, the mixture can be heated to a temperature of from about 60°C. to about 70° C. (e.g., about 65° C.). As another example, inembodiments in which the nozzle has a diameter of from about 100 micronsto about 200 microns and the desired viscosity of the mixture is fromabout 60 centipoise to about 100 centipoise, the mixture can be heatedto a temperature of from about 70° C. to about 80° C. (e.g., about 75°C.).

Drop generator 310 generates substantially spherical drops of apredetermined diameter by forcing a stream of the base polymer/gellingprecursor mixture through the nozzle orifice. The nozzle is subjected toa periodic disturbance to break up the jet stream of the mixture intodrops of the mixture. The jet stream can be broken into drops byvibratory action generated, for example, by an electrostatic orpiezoelectric element. The drop size can be controlled, for example, bycontrolling the nozzle orifice diameter, base polymer/gelling precursorflow rate, nozzle vibration amplitude, and nozzle vibration frequency.In general, holding other parameters constant, increasing the nozzleorifice diameter results in formation of larger drops, and increasingthe flow rate results in larger drops. Generally, holding otherparameters constant, increasing the nozzle vibration amplitude resultsin larger drops, and reducing the nozzle vibration frequency results inlarger drops. In general, the nozzle orifice diameter can be about 500microns or less (e.g., about 400 microns or less, about 300 microns orless, about 200 microns or less, about 100 microns or less) and/or about50 microns or more. The flow rate through the drop generator istypically from about one milliliter per minute to about 12 millilitersper minute. Generally, the nozzle frequency used can be about 0.1 KHz ormore (e.g., about 0.8 KHz or more, about 1.5 KHz or more, about 1.75 KHzor more, about 1.85 KHz or more, about 2.5 KHz or more, from about 0.1KHz to about 0.8 KHz). In general, the nozzle vibration amplitude islarger than the width of the jet stream. The drop generator can have avariable nozzle vibration amplitude setting, such that an operator canadjust the amplitude of the nozzle vibration. In some embodiments, thenozzle vibration amplitude is set at between about 80 percent and about100 percent of the maximum setting.

In some embodiments, drop generator 310 can charge the drops afterformation, such that mutual repulsion between drops prevents dropaggregation as the drops travel from drop generator 310 to gellingvessel 320. Charging may be achieved, for example, by an electrostaticcharging device such as a charged ring positioned downstream of thenozzle.

An example of a commercially available electrostatic drop generator isthe model NISCO Encapsulation unit VAR D (NISCO Engineering, Zurich,Switzerland). Another example of a commercially available drop generatoris the Inotech Encapsulator unit IE-50R/NS (Inotech AG, Dottikon,Switzerland).

Drops of the base polymer and gelling precursor mixture are captured ingelling vessel 320. The distance between gelling vessel 320 and theorifice of the nozzle in drop generator 310 is generally selected sothat the jet stream of the base polymer/gelling precursor mixture issubstantially broken up into discrete drops before reaching gellingvessel 320. In some embodiments, the distance from the nozzle orifice tothe mixture contained in gelling vessel 320 is from about five inches toabout six inches.

The mixture contained in gelling vessel 320 includes a gelling agentwhich interacts with the gelling precursor to stabilize drops by forminga stable gel. Suitable gelling agents include, for example, a divalentcation such as alkali metal salt, alkaline earth metal salt or atransition metal salt that can ionically cross-link with the gellingagent. An inorganic salt, for example, a calcium, barium, zinc ormagnesium salt can be used as a gelling agent. In embodiments,particularly those using an alginate gelling precursor, a suitablegelling agent is calcium chloride. The calcium cations have an affinityfor carboxylic groups in the gelling precursor. The cations complex withcarboxylic groups in the gelling precursor, resulting in encapsulationof the base polymer in a matrix of gelling precursor.

Without wishing to be bound by theory, it is believed that in someembodiments (e.g., when forming particles having a diameter of about 500microns or less), it can be desirable to reduce the surface tension ofthe mixture contained in gelling vessel 320. This can be achieved, forexample, by heating the mixture in gelling vessel 320 (e.g., to atemperature greater than room temperature, such as a temperature ofabout 30° C. or more), by bubbling a gas (e.g., air, nitrogen, argon,krypton, helium, neon) through the mixture contained in gelling vessel320, by stirring (e.g., via a magnetic stirrer) the mixture contained ingelling vessel 320, by including a surfactant in the mixture containingthe gelling agent, and/or by forming a mist containing the gelling agentabove the mixture contained in gelling vessel 320 (e.g., to reduce theformation of tails and/or enhance the sphericity of the particles).

FIG. 4 shows a photo-image of the gelled particles. As evident, a porestructure in the particle forms in the gelling stage. The concentrationof the gelling agent can affect pore formation in the particle, therebycontrolling the porosity gradient in the particle. Adding non-gellingions (e.g., sodium ions) to the gelling solution can reduce the porositygradient, resulting in a more uniform intermediate porosity throughoutthe particle. In embodiments, the gelling agent is, for example, fromabout 0.01 weight percent to about 10 weight percent (e.g., from aboutone weight percent to about five weight percent, about two weightpercent) in deionized water. In embodiments, particles, includinggelling agent and a pore structure, can be used in embolic compositions.

Following drop stabilization, the gelling solution can be decanted fromthe solid drops, or the solid drops can be removed from the gellingsolution by sieving. The solid drops are then transferred to reactorvessel 330, where the base polymer in the solid drops is reacted (e.g.,cross-linked) to produce precursor particles.

Reactor vessel 330 contains an agent that chemically reacts with thebase polymer to cause cross-linking between polymer chains and/or withina polymer chain. The agent diffuses into the solid drops from thesurface of the particle in a gradient which, it is believed, providesmore cross-linking near the surface of the solid drop than in the bodyand center of the drop. Reaction is greatest at the surface of a soliddrop, providing a stiff, abrasion-resistant exterior. For polyvinylalcohol, for example, vessel 330 includes one or more aldehydes, such asformaldehyde, glyoxal, benzaldehyde, aterephthalaldehyde, succinaldehydeand glutaraldehyde for the acetalization of polyvinyl alcohol. Vessel330 also includes an acid, for example, strong acids such as sulfuricacid, hydrochloric acid, nitric acid and weak acids such as acetic acid,formic acid and phosphoric acid. In embodiments, the reaction isprimarily a 1,3-acetalization:

This intra-chain acetalization reaction can be carried out withrelatively low probability of inter-chain cross-linking, as described inJohn G. Pritchard, “Poly(Vinyl Alcohol) Basic Properties and Uses(Polymer Monograph, vol. 4) (see p. 93-97), Gordon and Breach, SciencePublishers Ltd., London, 1970, which is incorporated herein byreference. Because the reaction proceeds in a random fashion, some OHgroups along a polymer chain might not react with adjacent groups andmay remain unconverted.

Adjusting for the amounts of aldehyde and acid used, reaction time andreaction temperature can control the degree of acetalization. Inembodiments, the reaction time is from about five minutes to about onehour (e.g., from about 10 minutes to about 40 minutes, about 20minutes). The reaction temperature can be, for example, from about 25°C. to about 150° C. (e.g., from about 75° C. to about 130° C., about 65°C.). Reactor vessel 330 can be placed in a water bath fitted with anorbital motion mixer. The cross-linked precursor particles are washedseveral times with deionized water to neutralize the particles andremove any residual acidic solution.

The precursor particles are transferred to dissolution chamber 340,where the gelling precursor is removed (e.g., by an ion exchangereaction). In embodiments, sodium alginate is removed by ion exchangewith a solution of sodium hexa-metaphosphate (EM Science). The solutioncan include, for example, ethylenediaminetetracetic acid (EDTA), citricacid, other acids, and phosphates. The concentration of the sodiumhexa-metaphosphate can be, for example, from about one weight percent toabout 20 weight percent (e.g., from about one weight percent to aboutten weight percent, about five weight percent) in deionized water.Residual gelling precursor (e.g., sodium alginate) can be measured byassay (e.g., for the detection of uronic acids in, for example,alginates containing mannuronic and guluronic acid residues). A suitableassay includes rinsing the particles with sodium tetraborate in sulfuricacid solution to extract alginate, combining the extract withmetahydroxydiphenyl colormetric reagent, and determining concentrationby UV/VIS spectroscopy. Testing can be carried out by alginate supplierssuch as FMC Biopolymer, Oslo, Norway. Residual alginate may be presentin the range of, for example, from about 20 weight percent to about 35weight percent prior to rinsing, and in the range of from about 0.01weight percent to about 0.5 weight percent (e.g., from about 0.1 weightpercent to about 0.3 weight percent, about 0.18 weight percent) in theparticles after rinsing for 30 minutes in water at about 23° C.

The particles are filtered through filter 350 to remove residual debris.Particles of from about 100 microns to about 300 microns can filteredthrough a sieve of about 710 microns and then a sieve of about 300microns. The particles can then be collected on a sieve of about 20microns. Particles of from about 300 to about 500 microns can filteredthrough a sieve of about 710 microns and then a sieve of about 500microns. The particles can then be collected on a sieve of about 100microns. Particles of from about 500 to about 700 microns can befiltered through a sieve of about 1000 microns, then filtered through asieve of about 710 microns, and then a sieve of about 300 microns. Theparticles can then be collected in a catch pan. Particles of from about700 to about 900 microns can be filtered through a sieve of 1000 micronsand then a sieve of 500 microns. The particles can then be collected ina catch pan. Particles of from about 900 to about 1200 microns canfiltered through a sieve of 1180 microns and then a sieve of 710microns. The particles can then be collected in a catch pan.

The particles are then packaged. Typically, from about one milliliter toabout five milliliters of particles are packaged in from about fivemilliliters to about ten milliliters of saline. The filtered particlesthen are typically sterilized by a low temperature technique, such ase-beam irradiation. In embodiments, electron beam irradiation can beused to pharmaceutically sterilize the particles (e.g., to reducebioburden). In e-beam sterilization, an electron beam is acceleratedusing magnetic and electric fields, and focused into a beam of energy.The resultant energy beam can be scanned by means of an electromagnet toproduce a “curtain” of accelerated electrons. The accelerated electronbeam penetrates the collection of particles, destroying bacteria andmold to sterilize and reduce the bioburden in the particles. Electronbeam sterilization can be carried out by sterilization vendors such asTitan Scan, Lima, Ohio.

The embolic compositions can be used in the treatment of, for example,fibroids, tumors, internal bleeding, AVMs, hypervascular tumors, fillersfor aneurysm sacs, endoleak sealants, arterial sealants, puncturesealants and occlusion of other lumens such as fallopian tubes. Fibroidscan include uterine fibroids which grow within the uterine wall(intramural type), on the outside of the uterus (subserosal type),inside the uterine cavity (submucosal type), between the layers of broadligament supporting the uterus (interligamentous type), attached toanother organ (parasitic type), or on a mushroom-like stalk(pedunculated type). Internal bleeding includes gastrointestinal,urinary, renal and varicose bleeding. AVMs are for example, abnormalcollections of blood vessels, e.g. in the brain, which shunt blood froma high pressure artery to a low pressure vein, resulting in hypoxia andmalnutrition of those regions from which the blood is diverted.

The magnitude of a dose of an embolic composition can vary based on thenature, location and severity of the condition to be treated, as well asthe route of administration. A physician treating the condition, diseaseor disorder can determine an effective amount of embolic composition. Aneffective amount of embolic composition refers to the amount sufficientto result in amelioration of symptoms or a prolongation of survival ofthe patient. The embolic compositions can be administered aspharmaceutically acceptable compositions to a patient in anytherapeutically acceptable dosage, including those administered to apatient intravenously, subcutaneously, percutaneously, intratrachealy,intramuscularly, intramucosaly, intracutaneously, intra-articularly,orally or parenterally.

In some embodiments, a composition containing the particles can be usedto prophylactically treat a condition.

Compositions containing the particles can be prepared in calibratedconcentrations of the particles for ease of delivery by the physician.Suspensions of the particles in saline solution can be prepared toremain stable (e.g., to not precipitate) over a duration of time. Asuspension of the particles can be stable, for example, for from aboutone minute to about 20 minutes (e.g. from about one minute to about tenminutes, from about two minutes to about seven minutes, from about threeminutes to about six minutes). The concentration of particles can bedetermined by adjusting the weight ratio of the particles to thephysiological solution. If the weight ratio of the particles is toosmall, then too much liquid could be injected into a blood vessel,possibly allowing the particles to stray into lateral vessels. In someembodiments, the physiological solution can contain from about 0.01weight percent to about 15 weight percent of the particles. Acomposition can include a mixture of particles, such as particles havingthe pore profiles discussed above, particles with other pore profiles,and/or non-porous particles.

While certain embodiments have been described, the invention is not solimited.

As an example, particles can be used for embolic applications withoutremoval of the gelling agent (e.g. alginate). Such particles can beprepared, for example, as described above, but without removing thealginate from the particle after cross-linking.

As another example, while substantially spherical particles arepreferred, non-spherical particles can be manufactured and formed bycontrolling, for example, drop formation conditions. In someembodiments, nonspherical particles can be formed by post-processing theparticles (e.g., by cutting or dicing into other shapes).

Moreover, in some embodiments the particles can include one or moretherapeutic agents (e.g., drugs). The therapeutic agent(s) can be inand/or on the particles. Therapeutic agents include agents that arenegatively charged, positively charged, amphoteric, or neutral.Therapeutic agents can be, for example, materials that are biologicallyactive to treat physiological conditions; pharmaceutically activecompounds; gene therapies; nucleic acids with and without carriervectors; oligonucleotides; gene/vector systems; DNA chimeras; compactingagents (e.g., DNA compacting agents); viruses; polymers; hyaluronicacid; proteins (e.g., enzymes such as ribozymes); cells (of humanorigin, from an animal source, or genetically engineered); stem cells;immunologic species; nonsteroidal anti-inflammatory medications; oralcontraceptives; progestins; gonadotrophin-releasing hormone agonists;chemotherapeutic agents; and radioactive species (e.g., radioisotopes,radioactive molecules). Non-limiting examples of therapeutic agentsinclude anti-thrombogenic agents; antioxidants; angiogenic andanti-angiogenic agents and factors; anti-proliferative agents (e.g.,agents capable of blocking smooth muscle cell proliferation);anti-inflammatory agents; calcium entry blockers;antineoplastic/antiproliferative/anti-mitotic agents (e.g., paclitaxel,doxorubicin, cisplatin); antimicrobials; anesthetic agents;anti-coagulants; vascular cell growth promoters; vascular cell growthinhibitors; cholesterol-lowering agents; vasodilating agents; agentswhich interfere with endogenous vasoactive mechanisms; and survivalgenes which protect against cell death. Therapeutic agents are describedin co-pending U.S. patent application Ser. No. 10/615,276, filed on Jul.8, 2003, and entitled “Agent Delivery Particle”, which is incorporatedherein by reference.

In addition, in some embodiments (e.g., where the base polymer is apolyvinyl alcohol and the gelling precursor is alginate), aftercontacting the particles with the gelling agent but beforecross-linking, the particles can be physically deformed into a specificshape and/or size. For example, the particles can be molded, compressed,punched, and/or agglomerated with other particles. After shaping, thebase polymer (e.g., polyvinyl alcohol) can be cross-linked, optionallyfollowed by substantial removal of the gelling precursor (e.g.,alginate). Particle shaping is described, for example, in co-pendingU.S. patent application Ser. No. 10/402,068, filed Mar. 28, 2003, andentitled “Forming a Chemically Cross-Linked Particle of a Desired Shapeand Diameter”, which is incorporated herein by reference.

Furthermore, in some embodiments the particles can be used for tissuebulking. As an example, the particles can be placed (e.g., injected)into tissue adjacent a body passageway. The particles can narrow thepassageway, thereby providing bulk and allowing the tissue to constrictthe passageway more easily. The particles can be placed in the tissueaccording to a number of different methods, for example, percutaneously,laparoscopically, and/or through a catheter. In certain embodiments, acavity can be formed in the tissue, and the particles can be placed inthe cavity. Particle tissue bulking can be used to treat, for example,intrinsic sphincteric deficiency (ISD), vesicoureteral reflux,gastroesophageal reflux disease (GERD), and/or vocal cord paralysis(e.g., to restore glottic competence in cases of paralytic dysphonia).In some embodiments, particle tissue bulking can be used to treaturinary incontinence and/or fecal incontinence. The particles can beused as a graft material or a filler to fill and/or to smooth out softtissue defects, such as for reconstructive or cosmetic applications(e.g., surgery). Examples of soft tissue defect applications includecleft lips, scars (e.g., depressed scars from chicken pox or acnescars), indentations resulting from liposuction, wrinkles (e.g.,glabella frown wrinkles), and soft tissue augmentation of thin lips.Tissue bulking is described, for example, in co-pending U.S. patentapplication Ser. No. 10/231,664, filed on Aug. 30, 2002, and entitled“Tissue Treatment”, which is incorporated herein by reference.

The following examples are intended as illustrative and nonlimiting.

Example 1

Particles were prepared as follows.

An aqueous solution containing eight weight percent polyvinyl alcohol(99+ percent hydrolyzed, average M_(w) 89,000-120,000 (Aldrich)) and twoweight percent sodium alginate (PRONOVA UPLVG, (FMC BioPolymer,Princeton, N.J.)) in deionized water was prepared. The solution washeated to about 121° C. The solution had a viscosity of about 310centipoise at room temperature and a viscosity of about 160 centipoiseat 65° C. Using a model PHD4400 syringe pump (Harvard Apparatus,Holliston, Mass.), the mixture was fed into a model NISCO Encapsulationunit VAR D drop generator (NISCO Engineering, Zurich, Switzerland).Drops generated by the drop generator were directed into a gellingvessel containing two weight percent calcium chloride in deionizedwater, and stirred with a stirring bar. The calcium chloride solutionwas decanted within about three minutes to avoid substantial leaching ofthe polyvinyl alcohol from the drops into the solution. The drops wereadded to a reaction vessel containing a solution of four weight percentformaldehyde (37 weight percent in methanol) and 20 weight percentsulfuric acid (95-98 percent concentrated). The reaction solution wasstirred at 65° C. for 20 minutes. Precursor particles were rinsed withdeionized water (3×300 milliliters) to remove residual acidic solution.The sodium alginate was substantially removed by soaking the precursorparticles in a solution of five weight percent sodiumhexa-methaphosphate in deionized water for 0.5 hour. The solution wasrinsed in deionized water to remove residual phosphate and alginate. Theparticles were filtered by sieving, as discussed above, placed in saline(USP 0.9 percent NaCl) and sterilized by irradiation sterilization.

Particles were produced at the nozzle diameters, nozzle frequencies andflow rates (amplitude about 80 percent of maximum) described in Table I.

TABLE I Flow Particle Nozzle Fre- Rate Size Diameter quency (mL/ DensitySphe- Suspendability (microns) (microns) (kHz) min) (g/mL) ricity(minutes) 500-700 150 0.45 4 — 0.92 3 700-900 200 0.21 5 1.265 0.94 5900-1200 300 0.22 10 — 0.95 6

Suspendability was measured at room temperature by mixing a solution oftwo milliliters of particles in five milliliters of saline with contrastsolution (Omnipaque 300, Nycomed, Buckinghamshire, UK), and observingthe time for about 50 percent of the particles to enter suspension(i.e., not to have sunk to the bottom or floated to the top of acontainer having a volume of about ten milliliters and a diameter ofabout 25 millimeters). Suspendability provides a practical measure ofhow long the particles will remain suspended in use.

Measurements were also made of the amount of time that the particlesremained suspended in the contrast solution. The particles remained insuspension for from about two to about three minutes.

Omnipaque 300 is an aqueous solution of Iohexol, N.N.-Bis(2,3-dihydroxypropyl)-T-[N-(2,3-dihydroxypropyl)-acetamide]-2,4,6-trilodo-isophthalamide.Omnipaque 300 contains 647 milligrams of iohexol equivalent to 300milligrams of organic iodine per milliliter. The specific gravity ofOmnipaque 300 is 1.349 of 37° C., and Omnipaque 300 has an absoluteviscosity 11.8 centipoise at 20° C.

Particle size uniformity and sphericity were measured using a BeckmanCoulter RapidVUE Image Analyzer version 2.06 (Beckman Coulter, Miami,Fla.). Briefly, the RapidVUE takes an image of continuous-tone(gray-scale) form and converts it to a digital form through the processof sampling and quantization. The system software identifies andmeasures particles in an image in the form of a fiber, rod or sphere.Sphericity computation and other statistical definitions are in AppendixA, attached, which is a page from the RapidVUE operating manual.

Referring to FIG. 5, particle size uniformity is illustrated forparticles having a diameter of from about 700 microns to about 900microns. The x-axis is the particle diameter, and the y-axis is thevolume-normalized percentage of particles at each particle size. Thetotal volume of particles detected was computed, and the volume of theparticles at each diameter was divided by the total volume. The embolicparticles had a distribution of particle sizes with variance of lessthan about ±15 percent.

Example 2

Particles were prepared as follows.

An aqueous solution containing 7.06 weight percent polyvinyl alcohol(99+ percent hydrolyzed, average M_(w) 89,000-120,000 (Aldrich)) and1.76 weight percent sodium alginate (PRONOVA UPLVG, (FMC BioPolymer,Princeton, N.J.)) was prepared. The solution was heated to about 121° C.The solution had a viscosity of about 140 centipoise at roomtemperature, and a viscosity of about 70 centipoise at 65° C. Using apressurized vessel, the mixture was fed to a drop generator (InotechEncapsulator unit IE-50R/NS, Inotech Biosystems International, Inc.).Drops generated by the drop generator were directed into a gellingvessel containing two weight percent calcium chloride in deionizedwater, and stirred with a stirring bar. The drops were collected withinabout three minutes to avoid substantial leaching of the polyvinylalcohol from the drops into the solution. The drops were added to areaction vessel containing a solution of four weight percentformaldehyde (37 weight percent in methanol) and 20 weight percentsulfuric acid (95-98 percent concentrated). The reaction solution wasstirred at 65° C. for 20 minutes. The precursor particles were rinsedwith deionized water (3×300 milliliters) to remove residual acidicsolution. The sodium alginate was substantially removed by soaking theprecursor particles in a solution of five weight percent sodiumhexa-methaphosphate in deionized water for half an hour. The solutionwas rinsed in deionized water to remove residual phosphate and alginate.The particles were filtered by sieving, placed in saline (USP 0.9percent NaCl) and sterilized by irradiation sterilization.

The particles were produced at the nozzle diameters, nozzle frequenciesand pressures (amplitude about 80 percent of maximum) described in TableII.

TABLE II Particle Nozzle Size Diameter Frequency Pressure Flow RateSuspendability (microns) (microns) (KHz) (Bar) (mL/min) (minutes)100-300 100 2.5 1.55 2.5 0.25 300-500 200 1.85 0.55 6.8 1

Suspendability was measured as described in Example 1.

Measurements were also made of the amount of time that the particlesremained suspended in the contrast solution. The particles remainedsuspended in the contrast solution for about 20 minutes.

FIG. 6 shows particle size uniformity for particles having a diameter offrom about 300 microns to about 500 microns (see discussion in Example1). The embolic particles had a distribution of particle sizes with avariance of less than about ±15 percent.

Example 3

Referring to FIG. 7, a catheter compression test was used to investigatethe injectability, and indirectly, the compressibility, of theparticles. The test apparatus included a reservoir syringe 610 and aninjection syringe 620 coupled to a T-valve 630. Reservoir syringe 610was a 20 milliliter syringe while injection syringe 620 was a threemilliliter syringe. T-valve 630 was coupled in series to a secondT-valve 640. T-valve 640 was coupled to a catheter 650 and a pressuretransducer 660. Injection syringe 620 was coupled to a syringe pump 621(Harvard Apparatus).

To test deliverability of the particles, syringes 610 and 620 wereloaded with embolic composition in saline and contrast agent (50/50Omnipaque 300). The embolic composition in syringes 610 and 620 wasintermixed by turning the T-valve to allow fluid between the syringes tomix and suspend the particles. After mixing, the embolic composition insyringe 620 flowed at a rate of about ten milliliters per minute. Theback pressure generated in catheter 650 was measured by the pressuretransducer 660 in millivolts to measure the clogging of catheter 650.About one milliliter of the particles was mixed in ten milliliters ofsolution.

Results for several different catheters (available from BostonScientific, Natick, Mass.) and particle sizes are shown in Table III.The baseline pressure was the pressure observed when injecting carrierfluid only. The delivery pressure was the pressure observed whiledelivering particles in carrier fluid. The average was the average ofthe peak pressure observed in the three runs.

TABLE III SIZE Inner Diameter Avg. Baseline Avg. Delivery Total number(microns) Delivery Catheter (microns) Pressure (psia) Pressure (psia) ofClogs 100-300 Spinnaker Elite ® 279 71.3 65.4 0 300-500 SpinnakerElite ® 330 54.6 52.6 0 500-700 RENEGADE ® 533 32.610 33.245 0 700-900FASTRACKER ® 609 11.869 13.735 0 900-1200 GLIDECATH ® 965 0.788 0.864 0

As evident, particles in each of the size ranges were successfullydelivered without clogging catheters with a lumen diameter smaller thanthe largest particle size. The particles exhibited a post-compressionsphericity of about 0.9 or more.

Example 4

Solubility was tested by mixing particles in a solution of solvent atroom temperature for about 0.5 hour and observing the mixture forvisible signs of dissolution. The particles were insoluble in DMSO(dimethylsulfoxide), HFIP (hexafluoro-isopropanol), and THF(tetrahydrofuran).

Example 5

Particles had the following glass transition temperatures, as measuredby differential scanning calorimetry data (DSC):

Size (microns) Glass Transition Temperature (° C.) 100-300 107-108300-500 110-111 500-700 109.30-110.14  900-1200 108.30-111.87

Example 6

FIGS. 8 and 9 show the ATR infrared spectra of dried particles preparedaccording to Examples 1 and 2, respectively.

Other embodiments are in the claims.

1.-31. (canceled)
 32. A particle having a diameter of about 500 micronsor less, wherein the particle comprises a cross-linked polymer, theparticle has a first density of pores in an interior region and a seconddensity of pores at a surface region, and the first density is differentfrom the second density.
 33. The particle of claim 32, wherein thepolymer comprises polyvinyl alcohol.
 34. The polymeric particle of claim32, wherein the first density is greater than the second density. 35.The polymeric particle of claim 32, wherein the particle has a firstaverage pore size in the interior region and a second average pore sizeat the surface region, the first average pore size being different fromthe second average pore size.
 36. The polymeric particle of claim 35,wherein the first average pore size is greater than the second averagepore size.
 37. The polymeric particle of claim 32, wherein the particlehas a diameter of about 10 microns or more.
 38. The polymeric particleof claim 32, wherein the particle has a diameter of about 100 microns ormore.
 39. The polymeric particle of claim 37, wherein the particle has adiameter of about 300 microns or less.
 40. The polymeric particle ofclaim 32, wherein the particle has a diameter of about 300 microns ormore.
 41. The polymeric particle of claim 32, wherein the polymercomprises at least one polymer selected from the group consisting ofpolyvinyl alcohols, polyacrylic acids, polymethacrylic acids, poly vinylsulfonates, carboxymethyl celluloses, hydroxyethyl celluloses,substituted celluloses, polyacrylamides, polyethylene glycols,polyamides, polyureas, polyurethanes, polyesters, polyethers,polystyrenes, polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids, andpoly(lactic-co-glycolic) acids.
 42. The polymeric particle of claim 32,wherein the particle is at least partially coated with a substantiallybioabsorbable material.
 43. The polymeric particle of claim 32, whereinthe particle has a density of from about 1.1 grams per cubic centimeterto about 1.4 grams per cubic centimeter.
 44. The polymeric particle ofclaim 32, wherein the particle has a sphericity of about 0.9 or more.45. The polymeric particle of claim 32, wherein, after compression toabout 50 percent, the particle has a sphericity of about 0.9 or more.46. The polymeric particle of claim 32, wherein the particle comprisesabout 2.5 weight percent or less polysaccharide.
 47. The polymericparticle of claim 46, wherein the polysaccharide comprises alginate. 48.The polymeric particle of claim 47, wherein the alginate has a guluronicacid content of about 60 percent or greater.
 49. The polymeric particleof claim 32, wherein the particle is substantially insoluble in DMSO.50. The polymeric particle of claim 32, wherein the particle issubstantially free of animal-derived compounds.
 51. A composition,comprising: a plurality of particles comprising a cross-linked polymer,at least some of the plurality of particles having a diameter of about500 microns or less, wherein at least some of the particles having adiameter of about 500 microns or less have a first density of pores inan interior region and a second density of pores at a surface region,the first density being different from the second density; and a carrierfluid, the plurality of particles being in the carrier fluid.